Alternative titles; symbols
HGNC Approved Gene Symbol: CLCF1
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38) : 11:67,364,168-67,374,177 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Cold-induced sweating syndrome 2 | 610313 | Autosomal recessive | 3 |
CLCF1 belongs to the interleukin-6 (IL6; 147620) family of cytokines, which are involved in cell signaling through phosphorylation of gp130 (IL6ST; 600694). IL6 family members share similarity in gene structure and have a 4-helix bundle in their protein structure (Senaldi et al., 1999).
Senaldi et al. (1999) cloned BSF3, which they also referred to as novel neurotrophin-1 (NNT1), by subtractive hybridization using a cDNA library prepared from phorbol ester-activated Jurkat T cells. The deduced protein contains 225 amino acids, including a 27-amino acid signal peptide. The mature form is predicted to be a 198-amino acid peptide with a molecular mass of 22 kD. BSF3 contains 4 cysteine residues, 2 of which are in the signal peptide, and 1 potential N-linked glycosylation site. The secondary structure is predicted to contain alpha helices. BSF3 shares 19 to 27% homology with other IL6 family members and 96% homology with mouse Bsf3. Northern blot analysis revealed a 2.2-kb transcript expressed predominantly in lymph nodes, spleen, peripheral blood lymphocytes, bone marrow, and fetal liver. Northern blot analysis of mouse tissues revealed strongest expression in lymph nodes, spleen, liver, lung, uterus, and ovary. N-terminal amino acid analysis of BSF3 expressed in HEK293 cells confirmed removal of the signal peptide.
Using cardiotrophin-1 (CTF1; 600435) as query in a database search, Shi et al. (1999) identified a full-length clone of CLC. CLC shares 29% identity with CTF1 and 20 to 26% identity with other neuropoietic cytokines. Northern blot analysis detected a 1.9-kb transcript expressed at high levels in spleen and peripheral blood leukocytes, at moderate levels in ovary, placenta, and kidney, and at low levels in colon, heart, lung, and pancreas. The transcript in lung was slightly smaller than that in other tissues. Shi et al. (1999) also detected CLC clones in cDNA libraries prepared from activated or resting neutrophils, bone marrow stromal cells, and synovial fibroblasts.
Senaldi et al. (1999) found that treatment of human neuroblastoma cells with recombinant BSF3 resulted in phosphorylation of gp130, LIFR-beta (151443), and STAT3 (102582). BSF3 supported the survival of chick embryo motor and sympathetic neurons in culture in a dose-dependent manner and induced growth of murine myeloid leukemia cells. Treatment of mice with recombinant BSF3 increased the level of serum amyloid A (104750), potentiated the induction of corticosterone and IL6 by IL1 (see 147760), and caused body weight loss and B-cell hyperplasia with elevated serum IgG and IgM levels.
Shi et al. (1999) found that recombinant CLC induced the activation of NFKB (see 164011) and SRE reporter constructs in several mammalian cell lines. The signal transduction pathway for CLC was characterized in a neuroblastoma cell line, and tyrosine phosphorylation of gp130 and STAT1 (600555), but not STAT3, was detected.
Senaldi et al. (1999) determined that the CLCF1 gene contains 3 exons and spans approximately 6 kb.
In an Australian man with Crisponi/cold-induced sweating syndrome (CISS2; 610313), Rousseau et al. (2006) identified compound heterozygosity for a truncating (607672.0001) and a missense mutation (607672.0002) in the CLCF1 gene. The mutations were not found in 140 control chromosomes.
In 2 Hungarian sisters with CISS2, Hahn et al. (2010) identified compound heterozygous mutations in the CLCF1 gene (607672.0003 and 607672.0004).
By FISH, Senaldi et al. (1999) mapped the CLCF1 gene to chromosome 11q13. By radiation hybrid analysis, Shi et al. (1999) mapped the CLCF1 gene to chromosome 11q13.3.
Using chick embryos, Forger et al. (2003) showed that administration of Clc enhanced motor neuron survival. There was no further enhancement through the addition of Cntf (118945) or Ctf1. Clc protected lumbar motor neurons, but not sensory neurons, from programmed cell death in embryonic chicks. Deletion of Clf (CRLF1; 604237) in mice resulted in reduced motor neurons and neonatal lethality. Both Clf and Clc were expressed in skeletal muscle fibers of embryonic mice. Forger et al. (2003) proposed that the CLC-CLF heterodimer is required for survival of specific pools of motor neurons.
Zou et al. (2009) observed decreased facial motility, failure to suckle, and death within 24 hours of birth in mice lacking Clc. The mutant mice also had nearly a third fewer motor neurons in the facial nucleus and ventral horn of the lumbar spinal cord. Zou et al. (2009) concluded that CLC is essential for motor neuron survival during development. They noted that the phenotype of Clc-knockout mice is concordant with those of mice lacking Cntfra or Clf, bolstering the hypothesis that CLC, along with CLF, is a component of the heterodimeric CNTFRA ligand (i.e., CNTFII).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human CLCF1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In an Australian man with Crisponi/cold-induced sweating syndrome-2 (CISS2; 610313), Rousseau et al. (2006) identified compound heterozygosity for a 321C-A transversion and a 590G-T transversion in the CLCF1 gene, resulting in a tyr107-to-ter (Y107X) and an arg197-to-leu (R197L; 607672.0002) substitution, respectively. The mutations were not found in 140 control chromosomes. Transfection studies demonstrated that truncated CLC containing a stop codon at position 107 cannot be correctly processed and expressed in mammalian cells. Functional studies of R197L CLC revealed an incapacity for the mutant protein to bind to CNTFR (118946) and activate subsequent signaling events; structural and docking interaction studies showed that the R197L substitution destabilized the contact site between CLC and CNTFR.
For discussion of the arg197-to-leu (R197L) mutation in the CLCF1 gene that was found in compound heterozygous state in a patient with Crisponi/cold-induced sweating syndrome-2 (CISS2; 610313) by Rousseau et al. (2006), see 607672.0001.
In 2 Hungarian sisters with Crisponi/cold-induced sweating syndrome-2 (CISS2; 610313), Hahn et al. (2010) identified compound heterozygosity for 2 mutations in the CLCF1 gene: a 46T-C transition resulting in a cys16-to-arg (C16R) substitution, and a 676T-C transition (607672.0004) resulting in the extension of the terminal stop codon by 171 residues (X226ext171).
For discussion of the 676T-C transition in the CLCF1 gene that was found in compound heterozygous state in 2 sisters with Crisponi/cold-induced sweating syndrome-2 (CISS2; 610313) by Hahn et al. (2010), see 607672.0003.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Forger, N. G., Prevette, D., deLapeyriere, O., de Bovis, B., Wang, S., Bartlett, P., Oppenheim, R. W. Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo. J. Neurosci. 23: 8854-8858, 2003. [PubMed: 14523086] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-26-08854.2003]
Hahn, A. F., Waaler, P. E., Kvistad, P. H., Bamforth, J. S., Miles, J. H., McLeod, J. G., Knappskog, P. M., Boman, H. Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood: four new cases. J. Neurol. Sci. 293: 68-75, 2010. [PubMed: 20400119] [Full Text: https://doi.org/10.1016/j.jns.2010.02.028]
Rousseau, F., Gauchat, J.-F., McLeod, J. G., Chevalier, S., Guillet, C., Guilhot, F., Cognet, I., Froger, J., Hahn, A. F., Knappskog, P. M., Gascan, H., Boman, H. Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. Proc. Nat. Acad. Sci. 103: 10068-10073, 2006. [PubMed: 16782820] [Full Text: https://doi.org/10.1073/pnas.0509598103]
Senaldi, G., Varnum, B. C., Sarmiento, U., Starnes, C., Lile, J., Scully, S., Guo, J., Elliott, G., McNinch, J., Shaklee, C. L., Freeman, D., Manu, F., Simonet, W. S., Boone, T., Chang, M.-S. Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Proc. Nat. Acad. Sci. 96: 11458-11463, 1999. [PubMed: 10500198] [Full Text: https://doi.org/10.1073/pnas.96.20.11458]
Shi, Y., Wang, W., Yourey, P. A., Gohari, S., Zukauskas, D., Zhang, J., Ruben, S., Alderson, R. F. Computational EST database analysis identifies a novel member of the neuropoietic cytokine family. Biochem. Biophys. Res. Commun. 262: 132-138, 1999. [PubMed: 10448081] [Full Text: https://doi.org/10.1006/bbrc.1999.1181]
Zou, X., Bolon, B., Pretorius, J. K., Kurahara, C., McCabe, J., Christiansen, K. A., Sun, N., Duryea, D., Foreman, O., Senaldi, G., Itano, A. A., Siu, G. Neonatal death in mice lacking cardiotrophin-like cytokine is associated with multifocal neuronal hypoplasia. Vet. Path. 46: 514-519, 2009. [PubMed: 19098279] [Full Text: https://doi.org/10.1354/vp.08-VP-0239-B-BC]